Phone: 001-352-392-8383
FAX: 001-352-392-6805

Phone: 0049 621 589-1906
Fax: 0049 621 589 1900

EXECUTIVE SUMMARY

INVEST is an investigator initiated international, prospective, randomized study comparing two pharmacotherapy strategies to control hypertension in ambulatory patients with coronary artery disease (DAD). One strategy, the calcium antagonist care strategy, centers on the calcium antagonist (verapamil SR) followed by addition of an ACE inhibitor (trandolapril) and then diuretic (hydrochlorothiazide) as needed to achieve target blood pressures (BP). The other strategy, the non-calcium antagonist care strategy, uses a bets-blocker (atenolol) followed by addition of low-dose diuretic and then an ACE inhibitor (trandolapril) as needed to reach target BP. In either strategy additional drugs can be added provided the calcium antagonist is retained in the calcium antagonist care strategy and calcium antagonists are omitted in the non-calcium antagonist care strategy.

The study is organized into 15 international regions with about 1,500 study investigators randomizing approximately 27,000 patients who will be treated for at least two years. The primary response variable is the occurrence of adverse outcome, defined as any of the following events: all cause mortality, nonfatal MI or nonfatal stroke. A number of secondary response variables will also be evaluated.

Unique features of INVEST are, in addition to its size and international scope, its design to mimic standard clinical practice and its all electronic online date entry, drug distribution system, study management system, and electronic physician compensation. This system will permit the entire trial to be conducted via the Internet. This design is believed to be a forerunner of clinical trials research for the future.

AIM OF THE STUDY

The primary objective of this trial is to examine the hypothesis that the risk for adverse outcomes (all cause mortality, nonfatal MI or nonfatal stroke) in hypertensive patients with CAD is at least equivalent during treatment of hypertension with a calcium antagonist strategy.

STUDY DESIGN

This is an international, multicenter, open, randomized, parallel-group design with a masked adverse outcome adjudication that uses two care strategies in outpatients with both hypertension and CAD cared for by primary care physicians. The hypertension care strategies use multiple drugs and are constructed to mimic standard clinical care. The care strategies consist of a calcium antagonist care strategy and a non-calcium antagonist care strategy.

The calcium antagonist care strategy utilizes verapamil SR, alone or in combination with an ACE inhibitor (trandolapril) and low dose diuretic (hydroclorothiazide) if needed, to control hypertension.

The non-calcium antagonist care strategy omits use of any calcium antagonists while hypertension management will be initiated by a bets-blocker (atenolol), alone or in combination with a diuretic (hydrochlorothiazide) and ACE inhibitor (trandolapril) if needed to control hypertension. Likewise, no calcium antagonists are permitted in this strategy for management of angina or other associated conditions (e.g., supraventricular tachyarrhythmias, gastrointestinal motility disorders, etc.).

After initial evaluation, randomization and dose titration, evaluations for occurrence of adverse outcome and adequacy of BP control are made at regularly scheduled visits at 6, 12, 18, 24, 52, 78 and at least 104 weeks after entry. If BP is in control for two consecutive 6-2eek visits, the next 6-week visit may be omitted.

TIME SCHEDULE

Prior to the start of the full phase of the study a pilot phase for testing the data management system and drug distribution system with approximately 150 patients will be started in September 1997.

Patient recruitment will start on or before December 31, 1997 and will last at least 6 months. The study should be completed in the 4^th quarter of 2000.

STUDY POPULATION

Number of patients

A total of approximately 27,000 randomized patients in approximately 1500 centers will be enrolled into the study.

The target population is outpatients with evidence for CAD who have a need for pharmacological treatment to manage hypertension and are cared for by primary care physicians. This population is composed principally of clinically stable elderly patients with hypertension and atherosclerotic CAD. Most of these patients have or have had angina pectoris and/or a remote myocardial infarction.

Inclusion criteria

1. Male or female
2. Age 50 to no upper limit
3. Hypertension documented according to the 6^th report of the Joint National Committee on Detection and Evaluation of the treatment of high B: (JNC VI) and the need for drug therapy (previously documented hypertension in patients currently taking antihypertensive agents is acceptable)
4. Documented CAD (e.g., classic angina pectoris (stable angina pectoris; Heberden angina pectoris), myocardial infarction three or more months ago, abnormal coronary angiography, or concordant abnormalities on two different types of stress tests)
5. Willingness to sign informed consent

Exclusion criteria

1. Unstable angina, angioplasty, CARBG or stroke within one month. Patients taking beta blockers after myocardial infarction are excluded if study enrollment is planned within 12 months of myocardial infarction. No time limitation if not taking beta-blocker.
2. Use of a b -blocker within past two weeks
3. Patients without a pacemaker and any of the following:
   Sinus bradycardia (<05 beats/min.)
   Sick sinus syndrome
   AV-block of more than 1^st degree
4. Documented contraindication to verapamil (appendix VII); documented contraindication to both atenolol and hydrochlorothiazide (appendix VII)
5. Atrial fibrillation/flutter with WPW-Syndrome
6. Severe heart failure (NYHA IV)
7. Concomitant illnesses (e.g., severe renal failure [Serum creatinine>=4.0 mg/dl], severe hepatic failure or known cirrhosis, etc.) which may affect outcome variables or where life expectancy is two years or less or which are likely to require frequent hospitalizations and/or treatment adjustments.
8. Patients with psychiatric, cognitive, or social (e.g., alcoholism, etc.) conditions that would interfere with giving consent, cooperating or remaining available for follow-up for two years

Study Layout

Visit 1

The purpose of visit 1 is eligibility determination and random assignment of eligible patients to one of the two hypertension care strategies. At this office visit subjects who appear to beet eligibility criteria (section 5.2/5.3) will be asked to sign an informed consent before baseline data will be entered and any treatment or change in treatment is initiated. Selected demographic, historical and physical examination data will be obtained. If the patient has angina the number of weekly episodes and nitroglycerine consumption will be recorded. The BP (section 6.4.2) and pulse rate will be determined.

Patients currently receiving a b -blocker are excluded (section 5.3).

Patients currently receiving other antihypertensive medication and whose blood pressure meets JNC-VI guidelines for blood pressure control must have their other antihypertensive medication discontinued prior to starting study medications.

Patients receiving antihypertensive agents other than calcium antagonists (diuretics, ACE-inhibitors, a-blockers, direct acting vasodilators, central acting agents) whose blood pressure does not meet JNC-VI guidelines can have these drugs continued at the discretion of the investigator and remain eligible.

Continuation of other medications is at the discretion of the study investigator.

While the site investigator/study nurse are expected to take notes during the visit, after the patient consent is obtained all data are to be entered directly into the interactive online electronic system using the preconfigured PC supplied to each site. After data entry, this system will print out the findings on a form which is to be added to the patient's permanent clinical record and this report will be the source document for visit 1. Eligible patients are identified and confirmed by the system and immediately randomized to a hypertension care strategy. A prescription containing the drug(s) for the randomly assigned care strategy is printed for investigator review and signature (Appendix III). For patients assigned to the calcium antagonist strategy this will be verapamil SR (Appendix IIa and IIb). Patients will also be given general instructions about non pharmacological management of the hypertension (appendix IIc) and secondary prevention of atherosclerosis (Appendix IIe). Data are transmitted electronically to the Data Coordinating Center (DCC) which then transmits the prescription to the Drug Distribution Center (DDC) to dispense medication. The patient is given a copy of the prescription listing the medication(s) to expect and the anticipated medication arrival date (two to three days in most cases). The patient will confirm that the medication was received by returning the post card verification in the medication shipment. This prepaid post card will be received by the DCC, where this information is added to the database. Another copy of the prescription is printed for the patient's clinical record.

In the rare event of unanticipated electronic data system failure, the above mentioned data are manually entered (visit findings form) and forms are faxed to the DCC (1-888-214-2169). In the event that both the electronic data system and fax fail the data may be transmitted by telephone (voice). The DCC will then enter the data to the database and transmit the randomly assigned medication assignment, for the specific site and patient back to the specific site for investigator review and signature. The investigator will confirm the prescription by return fax to the DCC and the DCC transmits these data to the DDC to have drugs dispensed to the patient.

Visit 2

Visit 2 will be scheduled approximately 6 weeks after visit 1. The purpose of visit 2 will be to evaluate the patient's response to randomly assigned medication and initiate medication titration when necessary. Inquiries are made about symptoms and any concurrent medication(s). Questions include angina frequency and symptoms that might be related to adverse clinical outcome or adverse experience (section 5.4). Compliance will be assessed from pill counts. Pulse rate and BP will be determined (section 6.4.2). Again all data will be entered directly to the online electronic system and a data printout serves as the source document for visit 2 to be entered into the patient's permanent record. Data will be transmitted simultaneously to the DCC. Prescriptions will be printed and inspected by the study investigator. If corrections re made (e.g., down titration for adverse effects) these are entered on-screen and a new prescription generated. The final prescription is transmitted to the Drug distribution Center and printed for investigator review. One copy will be kept in the patient's clinical record and one copy will be given to the patient as described above (section 6.1.2).

If BP does not meet the target goal which is mean sitting SBP/DBP < 140/ < 90 mmHg the next step of the hypertension care strategy (Appendix IIa and IIb) will be added at this visit (e.g., ACE inhibitor for those in the calcium antagonist care strategy or low-dose diuretic for those in the non-calcium antagonist care strategy).

If a patient in the non-calcium antagonist strategy was started on HCTZ 25 mg o.d. at visit 1 and blood pressure is not well controlled according to the JNC-VI the dose of HCTZ will be doubled to HCTZ 25 mg bid._

Visit 3 - 8

This visit will be scheduled after 12, 18, 24,52,78 and at least 104 weeks and a close out. Patients will be again evaluated each relative to BP control and clinical status. The evaluation will be essentially the same as in visit 2. Compliance will be again assessed from pill counts. If the patient meets BP goals without unacceptable adverse experiences assigned drugs will be continued. Patients whose BP is in control for the first two consecutive 6-233k visits, may omit the next two visits.

If BP does not meet target goal (mean sitting SBP/DBP < 140/ < 90 mmHg) and no unacceptable adverse experiences develop, the next step in the treatment strategy (Appendix IIb).

If BP goals are reached but unacceptable adverse experiences occur that are believed related to any of the randomized hypertension care strategy drugs those drugs will be down-titrated. In the patients randomized to the calcium antagonist care strategy, every attempt must be made to continue at least Isoptin SR 120 mg o.d.

Prescriptions will be printed and inspected by the study investigator. If corrections are made (e.g., down titration for adverse effects) these are entered on-screen and a new prescription generated. The final prescription is transmitted to the Drug Distribution Center and printed for investigator review. One copy will be kept in the patient's clinical record and one copy will be given to the patient as described above (section 6.1.2).

For specific details of the hypertension treatment strategies see Appendix IIa and appendix IIb.

Close-out visit

Every effort should be made to encourage all patients to remain in the study until close out.

Approximately two years after enrollment of the last patient the close out visit will be scheduled. This visit has to be performed within 6 weeks of notification. Every effort with be made to capture all information for the close out visit for every patient randomized. This will include telephone or mail contacts if needed.

For premature discontinuation of the study this visit may be conducted at any time and comprise the final evaluation. Compliance is again assessed from pill counts. In either case all patients will be given prescriptions for non study antihypertensive therapy as needed.

Outcome assessment

All outcome data are to be reported from the sites using a standardized on-line format. Adverse outcomes that are part of the primary response variable (death, nonfatal myocardial infarction and nonfatal stroke) are to be reported immediately (within 24 hours of investigators discovery) by the on-line system, FAX or phone to the INVEST Administrative Coordinating Center. In addition to the standardized report, INVEST sites are required to provide a brief summary which details onset date, resolution date (if possible) whether hospitalization or prolonged hospitalization was required, whether treatment was required for adverse outcome and the treatment outcome. The brief summary is to be accompanied by appropriate documentation (i.e., enzyme results, ECG, autopsy report, death certificate, hospital discharge report, etc.). The Administrative Center will forward all information on death, nonfatal myocardial infarction and nonfatal stroke to the Data Safety and Monitoring Committee (DSMC) masked to site and randomized care assignment. Outcome assessment will be adjudicated by the DSMC using a consensus opinion (see also section 6.5.3). Other adverse experiences comprising the secondary response variables will also require confirmatory clinical data or adjudication (section 7.3).

Visits and study procedure

Visits should be arranged for a given patient at approximately the same time of the day.

Table 1

§ There is a change in visit scheduling. After Visit 8, each visit will be scheduled at 6 month intervals (Req #1526). This visit schedule will be followed until a final cutoff point for the study is reached.
Return to schedule

The protocol requires calls for a total of eight scheduled patient visits and/or a final closeout visit. Table 1 lists procedures to be carried out at appropriate visits.

In accordance with JNC V/VI guidelines, any additional medical management visits that are needed are encouraged. These unscheduled medical management visits (identified as Visit 0) may be done in the physician's office or on the telephone. It is important that all Visit 0's be entered into the computer system.

Appendix I Flow Chart VeraTran

Copyright © 1997, 1998, 1999, 2000. University of Florida. All Rights Reserved.